Derivatives of asimadoline with covalently bonded acids

ABSTRACT

The present invention relates to derivatives of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide with covalently bonded acids, and to the salts, solvates and prodrugs thereof, to the derivatives as medicaments, to the use of these derivatives for the preparation of a medicament, to the use of these derivatives for the preparation of a pharmaceutical composition, to a process for the preparation of the pharmaceutical compositions, to pharmaceutical compositions obtainable by this process, and to a process for the treatment of diseases which comprises the administration of the pharmaceutical composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/539,256 filed Jun. 16, 2005 which is a national phase of PCTApplication No. PCT/EP2003/013206 internationally filed Nov. 25, 2003,which claims priority from European Patent Office Application No.10259245.4 filed Dec. 17, 2002. The contents of these documents areincorporated herein by reference in their entirety.

The present invention relates to derivatives ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidewith covalently bonded acids, to these derivatives as medicaments, tothe use of these derivatives for the preparation of a medicament, to theuse of these derivatives for the preparation of a pharmaceuticalcomposition, to a process for the preparation of the said pharmaceuticalcompositions, to pharmaceutical compositions obtainable by this process,and to a process for the treatment of diseases which comprises theadministration of the said pharmaceutical composition.

The compoundN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideand in particular the hydrochloride (EMD 61753) is known, for exampleunder the name asimadoline, and has already been described in EP-A-0 569802 (U.S. Pat. No. 5,532,226), EP-A-0 752 246 (U.S. Pat. Nos. 5,776,972and 5,977,161), DE-A-198 49 650, EP-A-0 761 650 (U.S. Pat. No.6,060,504) and EP-A-1 073 634 (U.S. Pat. No. 6,344,566). Thehydrochloride of this compound can be employed as a medicament activeingredient and exhibits a number of advantageous properties in variousindications.

The invention had the object of finding novel stable derivatives ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidewhich have better solubility, better absorption, greater stability,lower hygroscopy and/or improved pharmacokinetic properties.

Surprisingly, novel derivatives ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidehave now been found which exhibit advantageous properties compared withthe known administration forms, in particular compared withN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide,hydrochloride, as medicament active ingredient for a multiplicity ofindications. The advantageous properties of the derivatives according tothe invention preferably include improved solubility behaviour,modified, in particular improved pharmacokinetic behaviour, a modifiedtoleration profile and/or a modified half-value time, preferably anextended half-value time.

Surprisingly, the derivatives according to the invention interactintensively with the enterohepatic circulation. Thus, derivativesaccording to the invention can be cleaved, derivatised and/oradditionally metabolised by interactions with the enterohepaticcirculation or formed from freeN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide.Furthermore, a derivative according to the invention can be convertedinto another derivative according to the invention by interactions withthe enterohepatic circulation. It is assumed that at least some of theadvantageous properties of the derivatives according to the inventionarise due to interactions between a derivative according to theinvention and the enterohepatic circulation.

The present invention therefore relates to derivatives ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidewith at least one covalently bonded acid. This invention likewiserelates to the salts, solvates and prodrugs of the derivatives ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidewith at least one covalently bonded acid. For the purposes of theinvention, covalently bonded acid means that the derivative ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidecontains at least one acid, or a radical derived from an acid, which isnot bonded to theN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)-ethyl]-2,2-diphenylacetamideby an ionic interaction, in particular by salt formation. The derivativeaccording to the invention preferably comprises at least one acid, or aradical derived from an acid, which is bonded to theN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideby esterification or etherification.

The acid or the radical derived from an acid is preferably bonded to theN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidevia the 3-hydroxypyrrolidine group of theN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide.

Particular preference is therefore given to derivatives according to theinvention in which the acid or the radical derived from an acid iscovalently bonded to theN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)-ethyl]-2,2-diphenylacetamideby esterification or etherification with the 3-hydroxypyrrolidine group.N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidehas a free hydroxyl function in the 3-position of the pyrrolidine groupand is therefore an alcohol. The derivatives according to the inventionare therefore preferably the esters or ethers ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide,and very particularly preferably the esters or ethers ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidewith one of the acids listed below.

For the purposes of this invention, acids are, for example, inorganicacids, preferably inorganic oxygen acids, such as the oxygen acids ofthe halogens, of sulfur, of nitrogen and of phosphorus, particularlypreferably chloric acid, sulfurous acid, sulfuric acid, sulfamic acid,nitrous acid, nitric acid, phosphoric acids, preferably orthophosphoricacid, and organic acids, preferably aliphatic, alicyclic, araliphatic,aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic orsulfuric acids, particularly preferably methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids andlaurylsulfuric acid, very particularly preferably mono- or polybasiccarboxylic acids and mono- or polybasic hydroxycarboxylic acids, such asformic acid, acetic acid, propionic acid, pivalic acid, diethylaceticacid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleicacid, lactic acid, tartaric acid, malic acid, citric acid, gluconicacid, glucuronic acid, galacturonic acid, ascorbic acid, nicotinic acidand isonicotinic acid.

The acid is preferably selected from physiologically tolerated acids, inparticular from the physiologically tolerated acids of theabove-mentioned acids.

The acid is particularly preferably selected from carboxylic acids,hydroxycarboxylic acids and inorganic oxygen acids, very particularlypreferably from hydroxycarboxylic acids and inorganic oxygen acids.

The carboxylic acids are preferably selected from mono- or polybasiccarboxylic acids, preferably mono- or dibasic carboxylic acids, havingfrom 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms, such asthe monocarboxylic acids formic acid, acetic acid, propionic acid,diethylacetic acid, pivalic acid, nicotinic acid and isonicotinic acid,and the dicarboxylic acids malonic acid, succinic acid, pimelic acid,fumaric acid and maleic acid. The carboxylic acid is preferably aceticacid.

The hydroxycarboxylic acids are preferably selected frommonohydroxymonocarboxylic acids, such as lactic acid, monohydroxydi- or-polycarboxylic acids, such as malic acid and citric acid, andpolyhydroxymonocarboxylic acids, such as sugar acids, in particularascorbic acid, glucuronic acid and galacturonic acid.

The inorganic oxygen acids are preferably selected from sulfuric acid,orthophosphoric acid and nitric acid, preferably sulfuric acid andorthophosphoric acid and in particular sulfuric acid.

Particular preference is given to derivatives according to the inventionwhich contain at least one free acid group, i.e. an acid function whichis capable of salt formation or is in the form of a salt.

A preferred embodiment of the present invention therefore relates toderivatives according to the invention in which the acid is selectedfrom dibasic carboxylic acids, monobasic hydroxycarboxylic acids and atleast dibasic inorganic oxygen acids, in particular from the dibasiccarboxylic acids, monobasic hydroxycarboxylic acids and at least dibasicinorganic oxygen acids mentioned above as preferred.

A particularly preferred embodiment of the present invention relates toderivatives according to the invention in which the monobasichydroxycarboxylic acid is selected from sugar acids and is in particularglucuronic acid.

A further particularly preferred embodiment of the present inventionrelates to derivatives according to the invention in which the dibasicinorganic oxygen acid is sulfuric acid.

A particularly preferred embodiment of the present invention relates toderivatives according to the invention in which the acid is selectedfrom glucuronic acid and sulfuric acid.

The derivatives according to the invention are preferably selected fromthe esters of the above-mentioned monocarboxylic acids withN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideas alcohol component, the esters of the above-mentioned inorganic oxygenacids withN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideas alcohol component and the ethers of the above-mentionedhydroxycarboxylic acids withN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideas second alcohol component.

In the case of polybasic acid esters according to the invention, themonoesters are generally preferred. In the case of polyhydroxycarboxylicacid ethers according to the invention, the monoethers are generallypreferred. In general, theN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)-ethyl]-2,2-diphenylacetamidederivatives according to the invention and hydroxycarboxylic acids areessentially neither in the form of mixed esters and ethers of ahydroxycarboxylic acid, nor in the form of a mixture of two derivativesin which some of theN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideis bonded to the hydroxycarboxylic acid in the form of an ether and someof theN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideis bonded to the hydroxycarboxylic acid in the form of an ester.

Particularly preferred derivatives according to the invention aretherefore those which comprise at least 40% by weight, preferably atleast 60% by weight, particularly preferably at least 70% by weight,very particularly preferably at least 80% by weight or at least 90% byweight, at most 100% by weight, but in many cases less than 100% byweight, for example from 60 to 90% by weight, from 70 to 95% by weight,from 80 to 99.9% by weight or from 90 to 100% by weight, of a single,defined compound, which preferably comprises only one molecule or unitofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideas alcohol component and one molecule or unit of an acid, preferably oneof the above-mentioned acids, in covalently bonded form.

Examples of preferred derivatives according to the invention arecompounds of the formula I

in which R¹ is selected from

-   a) acyl radicals having from 1 to 12, preferably from 1 to 6, carbon    atoms, preferably alkanoyl radicals having from 1 to 12, preferably    from 1 to 6, carbon atoms and particularly preferably formyl,    acetyl, propionyl, isopropionyl, butyryl, isobutyryl and pivaloyl,    in particular acetyl;-   b) acyl radicals having from 1 to 12, preferably from 1 to 6, carbon    atoms which contain one hydroxyl group and/or one or more carboxyl    groups, and particularly preferably selected from

-   c) alkyl radicals derived from polyhydroxymonocarboxylic acids by    removal of a hydroxyl group, preferably from ascorbic acid,    glucuronic acid and galacturonic acid, particularly preferably

-   -   very particularly preferably

-   -   and in particular

-   -   and/or the open-chain forms thereof;    -   and from

-   d) sulfonic acid groups derived from sulfuric acid by removal of a    hydroxyl group, phosphonic acid groups derived from orthophosphoric    acid by removal of a hydroxyl group, and nitro groups derived from    nitric acid by removal of a hydroxyl group, in particular

-   -   and the salts and solvates thereof.

In the radicals R¹ reproduced under c) and d), the free bond or the freevalence preferably symbolises, for reasons of clarity, the point whereR¹ in the formula I is bonded to the oxygen atom. In the radicals R¹reproduced under c), the solid wedge preferably symbolises a bond whichpoints upwards with respect to the plane of the paper. In the radicalsR¹ reproduced under c), the hatched wedge preferably symbolises a bondwhich points downwards with respect to the plane of the paper.

Particularly preferred derivatives according to the invention areselected from compounds of the formula Ia

-   -   (6-((1S)-1-{[(2,2-diphenylethanoyl)methylamino]phenylethyl}-(3S)-pyrrolidin-3-yloxy)-D-glucuronic        acid)    -   and compounds of the formula Ib

-   -   (mono-((1S)-1-{[(2,2-diphenylethanoyl)methylamino]phenylethyl}-(3S)-pyrrolidin-3-yl)        sulfate)    -   and the salts and solvates thereof.

Preference is furthermore given to compounds of the formula (Ic)

-   -   (N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-acetoxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide)    -   and the salts and solvates thereof.

The invention also relates to pharmaceutically tolerated derivatives ofthe compounds according to the invention, in particular prodrugs andprodrug derivatives, salts and solvates of the compounds according tothe invention, in particular of the compounds of the formula I andsub-formulae thereof.

The invention also relates to the optically active forms(stereoisomers), preferably the enantiomers, the racemates and thediastereomers, and the hydrates and solvates of the compounds accordingto the invention. The term solvates of the compounds according to theinvention is taken to mean adductions of inert solvent molecules ontothe compounds according to the invention which form owing to theirmutual attractive force. Solvates are, for example, mono- or dihydratesor alcoholates.

The term prodrugs of compounds according to the invention is taken tomean derivatives according to the invention which have been modified bymeans of additional groups or contain additional groups. Preference isgiven to compounds of the formula I which have been modified by means ofadditional groups, for example alkyl or acyl groups, sugars oroligopeptides and which are rapidly cleaved in the organism to give theactive compounds according to the invention. These also includebiodegradable polymer derivatives of the compounds according to theinvention, as described, for example, in Int. J. Pharm. 115, 61-67(1995). Examples of prodrug derivatives of this type are the alkylesters of derivatives according to the invention which contain at leastone free acid group and the esters of derivatives according to theinvention which contain at least one free hydroxyl group.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.These are particularly preferably mixtures of stereoisomeric compounds.

Of the pharmaceutically tolerated derivatives, preference is given tothe salts and solvates of derivatives according to the invention, inparticular the derivatives of the formula I according to the invention,and in particular the physiologically tolerated salts and solvatesthereof.

A derivative according to the invention and in particular a compound ofthe formula I can be converted into a salt by the action of an acid orbase. Thus, a derivative according to the invention, in particular abasic derivative according to the invention, can be converted into theassociated acid-addition salt by means of an acid, for example byreaction of equivalent amounts of the base and the acid in an inertsolvent, such as ethanol, followed by evaporation. Suitable acids forthis reaction are, in particular, those which give physiologicallyacceptable salts. Thus, it is possible to use inorganic acids, forexample sulfuric acid, nitric acid, hydrohalic acids, such ashydrochloric acid or hydrobromic acid, phosphoric acids, such asorthophosphoric acid, sulfamic acid, furthermore organic acids, inparticular aliphatic, alicyclic, araliphatic, aromatic or heterocyclicmono- or polybasic carboxylic, sulfonic or sulfuric acids, for exampleformic acid, acetic acid, propionic acid, pivalic acid, diethylaceticacid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleicacid, lactic acid, tartaric acid, malic acid, citric acid, gluconicacid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- orethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and-disulfonic acids and laurylsulfuric acid. Salts with physiologicallyunacceptable acids, for example picrates, can be used for the isolationand/or purification of the derivatives according to the invention.

The acid employed for the formation of the acid-addition salt may beidentical to or different from the acid covalently bonded in thederivatives according to the invention, but the acid employed for theformation of the acid-addition salt is not covalently bonded in the salt(acid-addition salt), but instead is associated by ionic interactions.However, the acid covalently bonded in the derivative according to theinvention is preferably different from the acid used for the formationof the acid-addition salt. If a derivative according to the invention isin the form of a salt and in particular in the form of a physiologicallytolerated salt, this is generally an acid-addition salt and inparticular a physiologically tolerated acid-addition salt.

If the acid covalently bonded in the derivative according to theinvention contains one or more free acid groups, the derivativeaccording to the invention may be in the salt form as a so-calledinternal salt through internal salt formation, even without addition ofan acid or base. If the acid covalently bonded in the derivativeaccording to the invention is a physiologically tolerated acid andcontains one or more free acid groups, the derivative according to theinvention may be in the form of a physiologically tolerated salt throughinternal salt formation, even without addition of an acid or base.

Alternatively, a derivative according to the invention, in particular anacidic derivative according to the invention, can be converted into thebase-addition salt by means of a base, for example by reaction ofequivalent amounts of a derivative according to the invention and of abase in an inert solvent, such as ethanol, followed by evaporation.Suitable bases for this reaction are, in particular, those which givephysiologically acceptable salts. Suitable bases are known to the personskilled in the art. For example, derivatives according to the inventioncan be converted into the corresponding metal salts, in particularalkali metal salts or alkaline earth metal salts, or into thecorresponding ammonium salts, by means of bases, such as amines, alkalimetal hydroxides, alkaline earth metal hydroxides, alkali metalcarbonates and alkaline earth metal carbonates, preferably sodiumhydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.It is also possible to use physiologically acceptable organic bases,such as, for example, ethanolamine.

The present invention preferably relates to the derivatives according tothe invention in isolated and/or essentially pure form. Essentially purepreferably means that the derivatives according to the invention have ina purity of greater than 60% by weight, preferably greater than 80% byweight, particularly preferably greater than 90% by weight and inparticular greater than 95% by weight, such as, for example, greaterthan 97% by weight, greater than 99% by weight, greater than 99.9% byweight, greater than 99.99% by weight, or have a purity of up to 100% byweight. In mixtures of derivatives according to the invention, thepurity data preferably relate to the respective derivative and inparticular to the derivatives according to the invention present asprincipal constituents. In this connection, principal constituentspreferably denotes the derivatives according to the invention present inthe mixture which are present in the greatest proportion, where theproportion of a principal constituent in the mixture is preferably atleast 10% by weight, preferably at least 30% by weight, particularlypreferably at least 60% by weight and in particular at least 80% byweight, but less than 100% by weight, based on the total weight of thederivatives according to the invention present.

The derivatives according to the invention and/or the salts and solvatesthereof exhibit a number of valuable pharmacological properties. Thus,they preferably exhibit analgesic, neuroprotective, antiinflammatory,antiasthmatic, diuretic, anticonvulsive and/or antitussive actions,antagonise hyperalgesia, in particular inflammation-inducedhyperalgesia, protect against and are suitable for the treatment ofconditions of pain, cerebral oedema, conditions of undersupply of thecentral nervous system and in particular hypoxia, and for the treatmentand amelioration of the secondary damage after ischaemia, as described,for example, in EP-A-0 569 802, the disclosure content of which isexpressly incorporated herein by way of reference. Thus, experimentshave shown that the compounds according to the invention act on mice orrats in the “writhing test” (method, cf. Siegmund et al., Proc. Soc.Exp. Biol. 95, (1957), 729-731). The analgesic action as such canfurthermore be demonstrated in the “tail-flick test” on mice or rats(method, cf. d'Amour and Smith, J. Pharmacol. Exp. Ther. 72, (1941),74-79), furthermore in the “hot plate test” (cf. Schmauss and Yaksh, J.Pharmacol. Exp. Ther. 228, (1984), 1-12 and the literature citedtherein). Particularly strong actions can be observed in rats in themodel of carrageenan-induced hyperalgesia (cf. Bartoszyk and Wild,Neuroscience Letters 101 (1989) 95). At the same time, the compoundsexhibit no or only a slight tendency towards physical dependency. Inaddition, corresponding experiments carried out by customary methodshave demonstrated the pronounced antiinflammatory, diuretic,anticonvulsive and neuroprotective actions. The derivatives according tothe invention exhibit high affinity with respect to the bindingbehaviour to kappa-receptors.

A particular aspect of the present invention relates to the efficacy ofthe derivatives according to the invention for the prophylaxis and/ortreatment of functional gastrointestinal diseases, also calledfunctional gastric and/or intestinal diseases below or functionalgastric/intestinal diseases for short. The group of functionalgastrointestinal diseases is described in detail and classified in GUT:Rome II: A Multinational consensus Document on FunctionalGastrointestinal Disorders, Supplement II, Vol 45, 1999, the disclosurecontent of which is expressly incorporated herein by way of reference.

The functional gastrointestinal diseases are preferably selected fromfunctional gastroduodenal diseases, of which preferably functionalnausea and particularly preferably dyspepsia, in particular dyspepsianot associated with an ulcer; functional intestinal diseases, of whichpreferably functional abdominal pain, preferably functional wind orflatulence, particularly preferably functional obstipation, constipationor blockage, likewise particularly preferably functional diarrhea, andin particular irritable bowel, irritable colon or IBS (irritable bowelsyndrome); and chronic motility disorders.

The efficacy of the derivatives according to the invention in the saidindications or clinical pictures can be determined using standardmethods known from the prior art, or methods analogous thereto. Theindications and methods for the determination of the efficacy in theseindications are described, for example, in N. J. Talley, V.Stanghellini, R. C. Heading, K. L. Koch, J. R. Malagelada, G. N. J.Tytgat; Gut 1999; 45 (Suppl 2): II37-II42; W. G. Thompson, G. F.Longstreth, D. A. Drossman, K. W. Heaton, E. J. Irvine, S. A.Müller-Lissner; Gut 1999; 45 (Suppl 2): II43-II47; S. J. O. Veldhuyzenvan Zanten, N. J. Talley, P. Bytzer, K. B. Klein, P. J. Whorwell, A. R.Zinsmeister; Gut 1999; 45 (Suppl 2): II69-II77; M. Dapoigny, M. Homerin,B. Scherrer, B. Fraitag; Gut (34, Suppl. 3, S30, 1993); J.-L. Abitbol,B. Scherrer, C. de Meynard, G. Meric, B. Fraitag, Gut (39, Suppl. 3,A229-A230, 1996); and N. J. Talley, S. V. Van Zanten, L. R. Saez, G.Dukes, T. Perschy, M. Heath, C. Kleoudis, A. W. Mangel; AlimentaryPharmacology and Therapeutics 15: 4, 525-537; the disclosure content ofwhich is incorporated in full by way of reference.

The present invention therefore also relates to the use of thederivatives according to the invention for the diagnosis, prophylaxisand/or treatment of functional gastrointestinal diseases.

The present invention therefore preferably also relates to the use ofthe derivatives according to the invention for the preparation of amedicament for the diagnosis, prophylaxis and/or treatment of functionalgastrointestinal diseases.

In contrast to other compounds having a similar activity spectrum, thederivatives according to the invention are, in particular, particularlysuitable for the treatment of inflammatory intestinal diseases and foruse in pharmaceutical preparations for the treatment of inflammatoryintestinal diseases since, besides the analgesic and antiinflammatoryaction, they are suitable for normalising the intestinal motor systemimpairments caused by the disease. In particular, they are suitable forrestarting intestinal movements if there is a risk of intestinalobstruction due to the inflammatory intestinal disease, or it hasalready occurred. This action can also be employed for the treatment ofpostoperative ileus and the pain associated therewith. Inflammatoryintestinal diseases frequently result in colonalgia, digestive disordersand in the worst case intestinal obstruction. In particular, the latteris often associated with colic-like pain as a consequence of a strongcontraction stimulus, retention of faeces and flatus, vomiting and, withincreasing duration of the condition, dehydration, abdominal resistanceand finally shock. The derivatives according to the invention canadvantageously be employed for the treatment and amelioration of theabove-mentioned diseases or symptoms. In particular, they ameliorate thepain associated with inflammatory intestinal diseases and, in the acutecase of an intestinal blockage threatened or caused by the inflammatoryintestinal disease, can re-normalise or restart the intestinal motorsystem without causing detectable side effects, as described, forexample, in EP-A-0 752 246, the disclosure content of which is expresslyincorporated herein by way of reference.

The use of the derivatives according to the invention for the treatmentand/or prophylaxis of inflammatory intestinal diseases and in particularthe use of the derivatives according to the invention for thepreparation of a medicament for the treatment and/or prophylaxis ofinflammatory intestinal diseases is therefore a preferred aspect of thepresent invention.

The present invention also relates to the use of the derivativesaccording to the invention for the preparation of a medicament for thediagnosis, prophylaxis and/or treatment of neuropathy, the clinicalpictures and symptoms associated therewith and the diseases relatedthereto.

Neuropathy, or peripheral neuropathy, is a generally known term relatingto diseases of the peripheral nerves, usually nerve damage.

The peripheral nerve system consists of nerves which branch out of thespinal cord into all parts of the body. Nerve damage occurring in onlyone part of the body is known as mononeuropathy, nerve damage in anumber of areas as polyneuropathy. Radiculitis denotes neuropathyrelating to the nerve roots. If the disease occurs symmetrically on bothsides of the body, the state is referred to as symmetrical neuropathy.Peripheral neuropathy can occur as a consequence of diabetes, vitamindeficiency, HIV, cancer, viral diseases, alcohol abuse or as side effectof pharmaceuticals. It can therefore also be categorised by cause, suchas, for example, as diabetic neuropathy, food-induced neuropathy oralcohol-induced neuropathy. If a cause cannot be determined, the stateis called idiopathic neuropathy. Peripheral neuropathies are widespread,frequently have a considerable adverse effect on the general state ofhealth of the patient and not infrequently result in disabilities. Theaetiology, the clinical picture, the occurrence and/or the interactionswith other diseases have been discussed in detail in the literature, forexample in Boulton, Diabetes Metab 1998; 24 (Suppl 3): 55-65; IIIa, EurNeurol 1999; 41 (Suppl 1): 3-7; Lagueny, Rev Prat 2000; 50: 731-735;Peltier and Russell, Curr Opin Neurol 2002; 15: 633-638; Simpson, JNeurovirol 2002; 8 (Suppl 2): 33-41; Sweeney, Clin J Oncol Nurs 2002; 6:163-166; and Wulff and Simpson, Semin Neurol 1999; 19: 157-164). Thedisclosure content of the said publications and the references citedtherein is expressly incorporated herein by way of reference.

The most widespread complication of diabetes is neuropathy. It isestimated that up to 60 percent of diabetes patients develop neuropathyas a consequence of diabetes. Neuropathy is typically associated with awide range of symptoms, inter alia numbness or tingling, very unpleasantpins and needles sensation, the feeling of receiving a series ofelectric shocks, and pain of various types and severity. These symptomsmay occur individually or in combination.

The symptoms of diabetic neuropathy and in particular the painassociated therewith usually relates to the feet and ankles and to alesser extent the legs above the knee and the arms. Inadequate settingof the blood sugar level regularly results in nerve damage, which inturn results, with fair certainty, in the development of the clinicalpicture of diabetic neuropathy. The trigger of diabetic neuropathy isknown, namely diabetes mellitus, and it is assumed that it is associatedwith inadequate setting of the blood sugar level and the associatedhyperglycaemia. The higher the blood sugar level and the longer itremains above the norm, the more severe the disease will generally be.The precise mechanism of how increased blood sugar values result innerve damage still needs to be researched; other factors, such as, forexample, anomalies in nerve growth factors or the influence ofcardiovascular diseases (ischaemia, hypoxia) have likewise beenpostulated as important factors which contribute to the development ofdiabetic neuropathy (see, for example, Jude and Boulton, DiabetesReviews 1999; 7: 395-410; Dworkin, Clin J Pain 2002; 18: 343-349;Simmons and Feldman, Curr Opin Neurol 2002; 15: 595-603; Barbano et al.,Curr Pain Headache Rep 2003; 7: 169-177; Spruce et al., Diabet Med 2003;20: 88-98).

Surprisingly, it has been found that the derivatives according to theinvention can successfully be employed in the diagnosis, prophylaxisand/or treatment of neuropathy, the associated clinical pictures andsymptoms and related diseases.

In addition, the derivatives according to the invention preferablyaccelerate, as described herein, nerve regeneration and thereforeparticularly preferably accelerate or induce healing of the pathologicalstates or diseases described herein, such as, for example, partial orcomplete healing of neuropathy. In addition, the derivatives accordingto the invention preferably exhibit, as described herein, fewer sideeffects than the pharmaceuticals of the prior art.

The present invention therefore likewise preferably relates to the useof the derivatives according to the invention for the preparation of amedicament for the diagnosis, prophylaxis and/or treatment ofneuropathies, the clinical pictures and symptoms associated therewith,and related diseases.

For the purposes of the invention, the neuropathy is preferably selectedfrom diabetes-induced neuropathy, food-induced neuropathy,vitamin-deficiency-induced neuropathy, HIV-induced neuropathy,cancer-induced neuropathy, virus-induced neuropathies,alcohol-abuse-induced neuropathy and medicament-induced neuropathy,particularly preferably diabetes-induced neuropathy, food-inducedneuropathy and alcohol-abuse-induced neuropathy, and in particulardiabetes-induced neuropathies.

The derivatives according to the invention additionally exhibit highefficacy in neuropathies of other aetiology, and related diseases,clinical pictures or indications, such as, for example, neuralgia afterherpes infections, chemotherapy-induced neuropathy, vulvovaginitis;and/or lupus erythematodes. The activity or efficacy of the derivativesaccording to the invention in the prophylaxis and/or treatment of thesaid diseases can be demonstrated by methods known from the prior art oranalogously thereto, for example as described in Backonja and Glanzman,Clin Ther 2003; 25: 81-104; Bates and Timmins, Int J STD AIDS 2002; 13:210-212; Carrazana and Mikoshiba, J Pain Symptom Manage 2003; 25(5Suppl): S31-35; Harel et al., Pediatr Neurol 2002; 27: 53-56; Jensen,Eur J Pain 2002; 6 (Suppl A): 61-68; LaSpina et al. Eur J Neurol 2001;8: 71-75; Lersch et al., Clin Colorectal Cancer 2002; 2: 54-58; and/orMellegers et al., Clin J Pain 2001; 17: 284-295), or analogouslythereto. The disclosure content of the said publications and thereferences cited therein is expressly incorporated by way of reference.

The activity or efficacy of the derivatives according to the inventioncan be determined by processes or methods known from the prior art, oranalogously thereto. Suitable methods include experimental non-clinicalmethods, such as, for example, in-vitro assays, in-vivo assays, cellularassays and animal models, and clinical methods or clinical studies, butare not restricted thereto. Suitable methods are described, for example,in Field et al., Pain 1999; 80: 391-398; Miki et al., Eur J Pharmacol2001; 430: 229-234; Wallin et al., Eur J Pain 2002; 6: 261-272);Backonja, Epilepsia 1999; 40 (suppl 6): S57-59; Gorson et al., J NeurolNeurosurg Psychiatry 1999; 66: 251-252; Dallocchio et al., J PainSymptom Manage 2000; 20: 280-285; Hemstreet and Lapointe, Clin Ther2001; 23: 520-531; Brooks-Rock, Nurse Pract 2001; 26: 59-61; Backonjaand Glanzman, Clin Ther 2003; 25: 81-104; Kaul et al., Arch IntPharmacodyn Ther 1978; 234: 139-44; and Calcutt et al., Anesthesiology2000; 93: 1271-1278). The disclosure content of the said publicationsand the references cited therein is expressly incorporated by way ofreference.

For example, streptozotocin-induced diabetes in rats is regarded as asuitable animal model for the study of type 1 diabetes(insulin-dependent diabetes) and/or the secondary diseases and theassociated symptoms, in particular the secondary diseases describedherein and the associated symptoms (see, for example: Kaul et al., ArchInt Pharmacodyn Ther 1978; 234: 139-44; Calcutt et al., Anesthesiology2000; 93:1271-1278). In this model, even streptozotin-induced chronicdiabetes in rats results in sensory disorders, from thermal hypoalgesiato excessive behaviour responses to other sensory stimuli. Malnutritioncan increase the sensory nerve defects during diabetes.

In connection with the diagnosis, prophylaxis and/or treatment ofneuropathy, the associated clinical pictures and symptoms and therelated diseases and in particular the use of the derivatives accordingto the invention for the preparation of a medicament for use in thediagnosis, prophylaxis and/or treatment of neuropathy, the associatedclinical pictures and symptoms and the related diseases, reference ismade to the European patent application by the same applicant of Oct.30, 2003 with the European application number EP 03024781.1 and thesecondary international and European applications thereof, thedisclosure content of which is incorporated herein in full by way ofreference.

The derivatives according to the invention are furthermore suitable forthe treatment and/or prophylaxis of pain and oversensitivity to pain, inparticular occurring in back complaints, burn injuries, sunburn andrheumatic diseases, and the inflammatory reactions which occur therein.In particular, inflammatory processes in addition to the actual pain andpain oversensitivity reactions in these indications can also beinfluenced by the administration of suitable pharmaceutical preparationscomprising the derivatives according to the invention. The reflex ileuswhich occurs in the most severe burns can also be prevented or treated.The present invention likewise relates to the use of the derivativesaccording to the invention for the preparation of a medicament for thetreatment and/or prophylaxis of the above-mentioned diseases and/orsymptoms.

It has furthermore been found that the derivatives according to theinvention indicate an advantageous action in the treatment of allergies,in particular sun allergies, since allergic skin reactions subsiderapidly and the itching associated therewith reduces rapidly under theinfluence of the derivatives according to the invention. Positiveresults have equally been observed in the treatment of neurodermatitisand in particular pruritus (itching). In particular, the itching of theskin reduces in these diseases under the action of the derivativesaccording to the invention, and inflammatory skin reactions which occuror are stimulated by the disease are favourably affected. The presentinvention likewise relates to the use of the derivatives according tothe invention for the preparation of a medicament for the treatmentand/or prophylaxis of the above-mentioned diseases and/or symptoms.Particular preference is therefore given to the use of the derivativesaccording to the invention for the prophylaxis and/or treatment ofneurodermatitis, itching and in particular pruritus and in particularthe use for the preparation of a medicament for the treatment and/orprophylaxis of neurodermatitis, itching and in particular pruritus. Inthis connection too, the disclosure content of EP-A 0 752 246 isexpressly incorporated herein by way of reference.

The derivatives according to the invention are furthermore suitable forthe treatment of postoperative pain and pain oversensitivity reactionsand the ileus which frequently occurs after abdominal operations. Thepresent invention likewise relates to the use of the derivativesaccording to the invention for the treatment of and/or for thepreparation of a medicament for the treatment of the above-mentioneddiseases and/or symptoms.

The derivatives according to the invention can furthermore be employedand are effective for the treatment and/or prophylaxis ofnon-inflammatory diseases of the gastrointestinal tract, preferablynon-inflammatory intestinal diseases and in particular for the treatmentand/or prophylaxis of irritable bowel syndrome (IBS) since they cansimultaneously ameliorate the pain associated with this disease and curethe disease. It is advantageous here that the derivatives according tothe invention have no effects on normal intestinal peristalsis, but playa part in curing irritable bowel syndrome. The derivatives according tothe invention can thus advantageously be employed for the prophylaxis ofirritable bowel syndrome. In contrast to other compounds having asimilar activity spectrum, the derivatives according to the inventionand in particular the derivatives of the formula I are particularlysuitable for use in pharmaceutical preparations for the treatment ofirritable bowel syndrome since, besides the analgesic andantiinflammatory action, they are suitable for normalising theintestinal motor system impairments caused by the disease. In thisconnection, reference is made to DE 198 49 650, the entire disclosurecontent of which is incorporated herein by way of reference. Theefficacy of the derivatives according to the invention in theseindications can be demonstrated by methods known from the prior art, forexample as in Delgado-Aros et al., Am. J. Physiol. Gastrointest. LiverPhysiol. 284: G558-G566, 2003, or analogously thereto.

The use of the derivatives according to the invention for the treatmentand/or prophylaxis of non-inflammatory diseases of the gastrointestinaltract, preferably non-inflammatory intestinal diseases and particularlypreferably irritable bowel syndrome, is therefore a preferred aspect ofthe present invention. The use of the derivatives according to theinvention for the preparation of a medicament for the treatment and/orprophylaxis of non-inflammatory diseases of the gastrointestinal tract,preferably non-inflammatory intestinal diseases and particularlypreferably irritable bowel syndrome, is therefore a particularlypreferred aspect of the present invention.

In addition, the derivatives according to the invention exhibit at leastone of the following advantageous properties on administration topatients:

-   -   the derivatives according to the invention are effective as        modulators of the tonicity of the gastrointestinal tract; in        particular, they are suitable for effecting relaxation or        activation of the tonicity of the gastrointestinal tract; in        general, the modulating action of the derivatives according to        the invention is dose-dependent;    -   the derivatives according to the invention are suitable for        influencing the feeling of satiety and/or so-called postprandial        symptoms, for example the amount and/or severity of flatulence,        the sensation of repletion, nausea and/or pain after ingestion        of food;    -   the effects of the derivatives according to the invention on        satiety and/or postprandial symptoms are preferably        dose-dependent; in general, low doses result in a decrease in        the symptoms, while higher doses can result in an increase in        the symptoms;    -   the derivatives according to the invention can influence the        volume, in particular the uptake volume, and/or the tolerance,        for example to mechanical stimulation, of the gastrointestinal        tract and in particular of the colon; for example, the volume        can be significantly increased by the administration of low to        moderate doses compared with the state without administration of        a derivative according to the invention;    -   in general, the administration of the derivatives according to        the invention exhibits no or slight adverse effects on        functional parameters of the gastrointestinal tract, such as,        for example, the time of passage through the gastrointestinal        tract, gastric emptying, intestinal emptying and colonic        emptying; this effect is preferably not or only slightly        dose-dependent; the administration of the derivatives according        to the invention thus exhibits slight effects on the natural        function of the gastrointestinal tract and thus a low tendency        towards undesired side effects;    -   the administration of the derivatives according to the invention        in higher doses preferably results in an increase/strengthening        of the symptoms relating to the sensation of repletion; for        example, patients have the feeling of stomach fullness earlier        although they have taken less food and therefore eat less; the        derivatives according to the invention can thus be employed for        correction of the lack of a sensation of repletion in obese        patients and therefore for the treatment of obesity;    -   the derivatives according to the invention can furthermore be        employed and are effective for the treatment and/or prophylaxis        of eating disorders and/or digestive disorders, in particular        psychogenic eating disorders and/or psychogenic digestive        disorders, since they are suitable for advantageously        influencing or modulating the tonicity of the gastrointestinal        tract.

The derivatives according to the invention are therefore suitable forthe treatment and/or prophylaxis of eating and digestive disorders, inparticular psychogenic eating and digestive disorders, such aspathologically modified appetite, in particular loss of appetite orreduced appetite, as occurs, for example, in pregnancy, in the case ofcancer, in the case of infectious diseases, for example influenza orHIV, as a postoperative side effect, as a consequence of catabolism,cachexia, anorexia, in particular anorexia nervosa, dysorexia,dysponderosis, adipositas polyamine, obesity, gastroparesis, inparticular neurogenic gastroparesis, diabetic gastroparesis, myogenicgastroparesis or drug-induced gastroparesis, gastroatonia, gastroparesissolutions or enteroparesis, in particular after gastrointestinaloperations, and stenosis of the gastrointestinal tract, in particularstenosis of the pylorus.

The derivatives according to the invention are furthermore suitable foradministration as appetite suppressants, individually or in combinationwith other appetite suppressants, preferably with one or moresympathomimetics. Suitable further appetite suppressants orsympathomimetics are known to the person skilled in the art. Suitableappetite suppressants or sympathomimetics are, in particular,phenylpropanolamine, cathine, sibutramine, amfepramone, ephedrine andnorpseudoephedrine. In this connection, reference is made to EP 0 2011047.4, the full disclosure content of which is incorporated herein byway of reference.

The present invention therefore relates to the use of the derivativesaccording to the invention for the preparation of a medicament foradministration together with appetite suppressants which are differentfrom the derivatives according to the invention. The present inventiontherefore also relates to the use of the derivatives according to theinvention for the preparation of a combination medicament comprising atleast one further appetite suppressant.

The dose dependence of the advantageous effects of the derivativesaccording to the invention on the gastrointestinal tract can bedetermined easily by conventional methods, for example as described inEP 02011047.4, or analogously thereto. Relatively low doses (in mg ofactive ingredient, calculated as asimadoline, per kg of body weight) forthe purposes of this invention are preferably in the range from 0.001 to0.5 mg/kg daily, particularly preferably from 0.01 to 1.0 mg/kg dailyand in particular from 0.1 to 2.0 mg/kg daily, for example about 0.3mg/kg daily, about 0.75 mg/kg daily or about 1.0 mg/kg daily, whereasrelatively high doses for the purposes of the invention are generallyabove 2.0 mg/kg daily and preferably in the range from 2.25 to 5 mg/kgdaily and in particular in the range from 2.5 mg/kg to 10 mg/kg daily,for example about 3 mg/kg daily, about 5 mg/kg daily or about 8 mg/kgdaily.

In addition, there are indications that the derivatives according to theinvention can advantageously be employed for the treatment of eye pain,in particular for the topical treatment of eye pain, irrespective of thegenesis of the eye pain. The derivatives according to the invention canparticularly advantageously be employed for the topical treatment ofpostoperative eye pain, as can occur, for example, after operations bymeans of lasers and in particular after so-called PRK operations. PRKhere stands for photorefractive keratotomia.

There are furthermore indications that the derivatives according to theinvention can advantageously be employed for the treatment of ear pain,in particular for the topical or intranasal treatment of ear pain,irrespective of the genesis of the ear pain. The derivatives accordingto the invention can particularly advantageously be employed for thetreatment of ear pain, as can occur, for example, in otitis, infections,inflammation, in particular middle-ear inflammation, oedema, accidenttraumas, operations and postoperatively.

The derivatives according to the invention can preferably advantageouslybe employed for the treatment and/or prophylaxis of dyspepsia, inparticular of dyspepsia which is not associated with an ulcer (non-ulcerdyspepsia or NUD).

The derivatives according to the invention can furthermore preferablyadvantageously be employed for the treatment and/or prophylaxis ofneuropathy, in particular diabetic neuropathy.

For the purposes of the invention, diseases or indications are thereforepreferably selected from pain, conditions of pain, ear pain, eye pain,inflammation, ileus, inflammatory intestinal diseases, irritable bowelsyndrome, irritable bladder syndrome, dyspepsia, neuropathy, adipositas,bulimia, obesity, cachexia, anorexia, dysorexia, dysponderosis,gastroparesis and stenosis of the gastrointestinal tract.

The present invention therefore relates to the use of a derivativeaccording to the invention and/or a salt or solvate thereof for theprevention and/or treatment of diseases, in particular one or more ofthe diseases or indications mentioned herein.

The present invention therefore preferably relates to the use of aderivative according to the invention and/or a salt or solvate thereoffor the preparation of a medicament for the prevention and/or combatingof diseases, in particular one or more of the diseases or indicationsmentioned herein.

In addition, it has proven particularly advantageous in the case of thederivatives according to the invention that, in spite of theiradvantageously modified property profile as described above, they areapparently unable to cross the blood-brain barrier and therefore have nopotential for dependence. In addition, no effects have hitherto beenfound which would in any way restrict the use of the advantageousactions for the claimed indications. This is particularly surprisingsince the derivatives according to the invention generally haverelatively high, preferably even greatly increased polarity and/orhydrophilicity, which generally greatly increases the ability to crossthe blood-brain barrier.

The present invention therefore relates to the use of the derivativesaccording to the invention for the preparation of a medicament for thetreatment and/or prophylaxis of the above-mentioned diseases.

The present invention therefore also relates to a pharmaceuticalpreparation which comprises at least one of the derivatives according tothe invention and/or a solvate or salt thereof. The pharmaceuticalpreparations according to the invention preferably comprise, based onthe total weight of the pharmaceutical preparation, at least 0.001% byweight, particularly preferably at least 0.01% by weight, veryparticularly preferably at least 0.1% by weight and in particular atleast 1.0% by weight of at least one derivative according to theinvention and/or a solvate or salt thereof. In general, the preparationsaccording to the invention comprise at most 100% by weight andpreferably at most 98% by weight or at most 95% by weight of derivativesaccording to the invention. In general, the pharmaceutical preparationsaccording to the invention comprise at least 5% by weight, for exampleat least 15% by weight or at least 30% by weight of further componentswhich are different from the derivatives according to the invention andthe salts and solvates thereof, preferably selected from further activeingredients and the conventional constituents, other than activeingredients, which are generally present in pharmaceutical preparations.Examples of further components of this type other than activeingredients are described herein. Examples of further active ingredientsof this type which are different from the derivatives according to theinvention and the salts and solvates thereof are described herein.

The derivatives according to the invention are preferably prepared infull or in part by conventional chemical synthetic methods,biotechnological methods or genetic engineering methods. In thepreparation of the derivatives according to the invention, at least thecovalent bonding between theN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideand the covalently bonded acid is preferably carried out by means ofconventional chemical synthetic methods. A suitable conventionalchemical synthetic method is described below.

The invention furthermore relates to a process for the preparation ofthe derivatives according to the invention and physiologicallyacceptable salts thereof, characterised in that

-   a) a compound of the formula II

-   -   in which    -   L¹ is H or a metal ion;

-   b) is reacted with a compound of the formula III    R¹-L²  III    -   in which    -   L² is a leaving group, preferably selected from Cl, Br, I, OH,        SR³, a reactively esterified OH group, an imidazolide group, a        carboxylate group and a diazonium group, R³ is alkyl, aralkyl or        aryl, and R¹ is as defined above and below for the compounds of        the formula or, if        -   R¹ contains one or more functional groups, preferably one or            more functional groups, selected from hydroxyl groups and            carboxyl groups, in addition to the group L²,        -   a derivative of R¹ which is provided fully or partly with            protecting groups,

-   c) where appropriate, one or more protecting groups are cleaved off    from R¹ if the product of the reaction of a) and b) contains one or    more protecting groups; if desired, the compound of the formula I is    isolated,

-   d) the resultant compound of the formula I is converted into one of    its salts by treatment with an acid or base, and, if desired, the    salt is isolated.

In the compounds of the formula II, L¹ is preferably H or a metal ion.Suitable metal ions are, in particular, alkali metal, alkaline earthmetal or aluminium ions. Preferred metal ions are alkali metal ions, inparticular Li, Na or K. L¹ is particularly preferably H.

In the compounds of the formula III, R¹ is preferably selected from

-   a) acyl radicals, as described above for the compounds of the    formula I-   b) acyl radicals which contain a hydroxyl group and/or one or more    carboxyl groups, as described above for the compounds of the formula    I,-   c) alkyl radicals derived from polyhydroxymonocarboxylic acids, as    described above for the compounds of the formula I, and-   d) sulfonic acid groups, phosphonic acid groups and nitro groups as    described above for the compounds of the formula I.

In the compounds of the formula III, L² is a suitable leaving group.Suitable leaving groups are known to the person skilled in the art, forexample from Houben-Weyl, Methoden der organischen Chemie [Methods ofOrganic Chemistry], Thieme-Verlag, Stuttgart. Besides the halides F, Cl,Br and I and reactively esterified OH groups, examples of suitableleaving groups are in particular imidazolides, acid anions derived fromacid anhydrides, as formed, for example, if the compound of the formulaIII employed is a mixed or asymmetrical or symmetrical acid anhydride,and diazonium groups, as can be obtained, for example, by diazotisationof amines by conventional methods.

For the purposes of the invention, reactively esterified OH groups arepreferably alkylsulfonyloxy groups having 1-6 carbon atoms (preferablymethylsulfonyloxy) or arylsulfonyloxy groups having 6-10 carbon atoms(preferably phenyl- or p-tolylsulfonyloxy).

In many cases, the compound of the formula III advantageously employedin the process according to the invention is an acid halide, preferablyan acid halide derived from the above-mentioned acids. Suitable acidhalides of the above-mentioned acids and processes for their preparationare known to the person skilled in the art. The acid halide ispreferably chlorosulfonic acid.

In many cases, the compound of the formula III advantageously employedin the process according to the invention is an acid anhydride,preferably an acid anhydride which is derived from the above-mentionedacids or contains at least one of the acids mentioned above/below forthe preparation of the derivatives according to the invention. Suitableacid anhydrides for the preparation of the derivatives according to theinvention by the process according to the invention are known to theperson skilled in the art. The acid anhydride is preferably aceticanhydride.

In the compounds of the formula III, L² is preferably selected from Cl,Br and SR³ and is in particular Br.

In the compounds of the formula III, L² is preferably not OH and/or adiazonium group.

In the compounds of the formula III in which L² is SR³, R³ is preferablyselected from branched or unbranched alkyl radicals having from 1 to 10carbon atoms, such as, preferably, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, in particular ethyl, aralkyl radicalshaving from 6 to 10 carbon atoms, such as benzyl, and aryl radicalshaving from 6 to 10 carbon atoms, such as phenyl, p-nitrophenyl andp-tolyl. Particular preference is given to methyl, ethyl, isopropyl,n-butyl, isobutyl, phenyl and benzyl. Preferred groups SR³ are selectedfrom S—C₂H₅, S—CH(CH₃)₂, S—C₆H₅ and S.CH₂—C₆H₅.

The process according to the invention can be carried out in the absenceor presence, preferably in the presence, of a suitable solvent,preferably one which is inert under the reaction conditions. Suitablesolvents are known to the person skilled in the art. Preferred solvents,in particular for reaction steps a) and b), are polar, aprotic solvents,such as acetonitrile, tetrahydrofuran (THF), 1,4-dioxane anddichloromethane. Particularly suitable solvents for reaction steps c)and/or d) are the solvents which have been proposed for the removal ofthe respective protecting group.

The reaction times for the process according to the invention aregenerally between a few minutes and a few days, preferably between 30minutes and 48 hours and in particular between one hour and 24 hours.

The reaction temperatures for the process according to the invention aregenerally between −20° C. and 100° C., preferably between −10° C. and60° C., particularly preferably between 0° C. and 40° C., for exampleabout room temperature (25° C.).

The process according to the invention can be carried out in thepresence of adjuvants which positively influence the reaction rate, theselectivity and/or the yield of the process according to the invention.Examples of assistants of this type are auxiliary bases, catalysts andsubstances which remove at least one of the resultant products and/orby-products from the process. Suitable assistants of this type are knownto the person skilled in the art, for example from Houben-Weyl, Methodender organischen Chemie [Methods of Organic Chemistry].

If use is made of a compound of the formula III in which L² is halogenand in particular chlorine or bromine, it may be advantageous, whencarrying out the process according to the invention, to add a silversalt which removes the halide liberated during the reaction according tothe invention of the compound of the formula II with a compound of theformula III from the process in the form of a low-solubilityprecipitate. Suitable silver salts are known to the person skilled inthe art, for example silver nitrate, silver carbonate and silverperchlorate. The silver salt is preferably silver perchlorate.

If use is made of a compound of the formula III in which L² is SR³, itmay be advantageous when carrying out the process according to theinvention to add an N-halosuccinimide, in particular N-iodosuccinimide,and/or a halocarboxylic acid, in particular trifluoroacetic acid.

If the radical R¹ in the compound of the formula III contains furtherfunctional groups (in addition to the group L²), in particular furtherhydroxyl groups and/or acid groups, it is in many cases advantageous toemploy a so-called protected derivative, i.e. a derivative provided withone or more protecting groups, of a radical R¹ as described above in theprocess according to the invention. The further functional groups hereare advantageously protected by means of the usual protecting groups forthe respective functional group. Suitable protecting groups andprocesses for the preparation of protected derivatives of this type areknown to the person skilled in the art. Hydroxyl groups are preferablyprotected with hydroxyl-protecting groups, acid groups preferably withacid-protecting groups.

The term “hydroxyl-protecting group” is known in general terms andrelates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but which are easily removable after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are the above-mentioned unsubstitutedor substituted aryl, aralkyl or acyl groups, furthermore also alkylgroups. The nature and size of the hydroxyl-protecting groups are notcrucial since they are generally removed again after the desiredchemical reaction or reaction sequence; preference is given to groupshaving 1-20, in particular 1-10, carbon atoms. Examples ofhydroxyl-protecting groups are, inter alia, benzyl, p-nitrobenzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where acetyl, benzyl andtert-butyl and especially acetyl are particularly preferred. Protectedhydroxyl groups are thus generally in the form of ether groups and/orester groups.

The term “acid-protecting group” is likewise known in general terms andrelates to groups which are suitable for protecting an acid group,preferably a carboxylic acid group or an acid group of an inorganicoxygen acid, in particular the acid groups of the above-mentioned acids,against chemical reactions, but which are easily removable after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are unsubstituted or substituted,preferably unsubstituted aryl, aralkyl or alkyl groups. Protected acidgroups are thus preferably in the form of the aryl, aralkyl or alkylesters, particularly preferably aralkyl or alkyl esters, of the saidacid groups. Preferred acid-protecting groups are the methyl group, thetert-butyl group and the benzyl group, particularly preferably themethyl group. Esters can, for example, be saponified using acetic acidor using NaOH or KOH in water, water/THF or water/dioxane attemperatures between 0 and 100°.

The liberation of the protected derivatives according to the inventionand in particular protected compounds of the formula I is carriedout—depending on the protecting group used—either using acids,preferably strong acids, advantageously using TFA or perchloric acid,but also using other strong inorganic acids, such as hydrochloric acidor sulfuric acid, strong organic carboxylic acids, such astrichloroacetic acid, or sulfonic acids, such as benzene- orp-toluenesulfonic acid, or bases, preferably strong bases, such asamines, alkali metal hydroxides, alkaline earth metal hydroxides, alkalimetal carbonates and alkaline earth metal carbonates, preferably sodiumhydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.The base is preferably sodium hydroxide, for example an aqueous sodiumhydroxide solution. The presence of an additional inert solvent ispossible, but is not always necessary. Suitable inert solvents arepreferably organic, for example carboxylic acids, such as acetic acid,ethers, such as tetrahydrofuran or dioxane, amides, such as DMF,halogenated hydrocarbons, such as dichloromethane, furthermore alsoalcohols, such as methanol, ethanol or isopropanol, and water. Alsosuitable are mixtures of the above-mentioned solvents. TFA is preferablyused in excess without addition of a further solvent, and perchloricacid is preferably used in the form of a mixture of acetic acid and 70%perchloric acid in the ratio 9:1. The reaction temperatures for thecleavage are advantageously between about 0 and about 50°, preferablybetween 15 and 30°, for example room temperature.

Esters and/or ethers can, for example, advantageously be saponifiedusing acetic acid or in particular using NaOH or KOH in water, water/THFor water/dioxane at temperatures between 0 and 100°, preferably at aboutroom temperature (25° C.).

Hydrogenolytically removable protecting groups (for example benzyl) canbe cleaved off, for example, by treatment with hydrogen or ahydrogen-liberating compound, for example ammonium formate, in thepresence of a catalyst (for example a noble-metal catalyst, such aspalladium, advantageously on a support, such as carbon). Suitablesolvents here are solvents as are usually used in hydrogenations, inparticular, for example, alcohols, such as methanol or ethanol, ethers,such as diethyl ether, tetrahydrofuran (THF) or 1,4-dioxane, or amides,such as DMF. The hydrogenolysis is generally carried out at temperaturesbetween about 0 and 100° and pressures between about 1 and 200 bar,preferably at 20-30° C. and 1-10 bar.

The protected compound of the formula III, i.e. the compound of theformula III provided with one or more protecting groups, is particularlypreferably a compound of the formula IIIa or IIIb

in which each radical R′ and R″, independently of one another, isselected from H, branched and unbranched alkyl radicals having from 1 to10 carbon atoms, aralkyl radicals having from 6 to 10 carbon atoms andaryl radicals having from 6 to 10 carbon atoms, preferably methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, benzyl,p-nitrophenyl and p-tolyl, particularly preferably methyl, benzyl andtert-butyl and in particular methyl, with the proviso that at least oneof the radicals R′ and R″ is not H. Preferably, a plurality of theradicals R′ and R″ and in particular all radicals R′ and R″ are not H.Very particular preference is given to compounds of the formula IIIb inwhich R′ and R″ are methyl.

The protected compound of the formula III, i.e. the compound of theformula III provided with one or more protecting groups, is thereforeparticularly preferably a compound of the formula IIIc

in which the abbreviation Ac is an acetyl radical, and Me is a methylgroup. In the formulae IIIa, IIIb and IIIc, L² is preferably Br.

Compounds of the formula III in which L² is SR³ or S—C(O)—R³ can beobtained by known methods. For example, they can be prepared by themethod described by Arie L. Gutman et al., Synthesis 2000, 1241-1246, oranalogously thereto.

The protected compound of the formula III, i.e. the compound of theformula III provided with one or more protecting groups, is thereforelikewise preferably a compound of the formula IIId or IIIe

in which R′ and R³ are as defined above, and in particular in which R′in the formula IIId is benzyl and R′ in the formula IIIe is isopropyl.R³ is preferably ethyl or phenyl.

Compounds of the formula IIId or Ille can be obtained, for example,starting from compounds of the formula IIIa or IIIb and in particularfrom compounds of the formula IIIc, in particular those in which L² ishalogen, where, in a first step, a radical L² which is not SR³ isconverted into a radical L² which is SR³, for example by substitutionand in particular by nucleophilic substitution.

The process according to the invention can be carried out as a one-potreaction, i.e. isolation and/or purification steps are omitted as far aspossible and only the desired end product, i.e. generally a derivativeaccording to the invention or a protected derivative thereof, preferablya derivative according to the invention and in particular a compound ofthe formula I, is purified and/or isolated. Alternatively, apurification and/or isolation step can be carried out after each of thesaid reaction steps. Mixed forms of the procedure described above arealso conceivable.

Suitable purification and isolation steps are known to the personskilled in the art, for example from Houben-Weyl, Methoden derorganischen Chemie [Methods of Organic Chemistry].

If, as in process step b) of the process according to the inventiondescribed above, use is made of a compound of the formula III in whichR¹ is in the form of a derivative which is provided fully or partly withprotecting groups, but use is made of the option under process step c)and the protecting groups of R¹ are not cleaved off or are not cleavedoff completely, a derivative according to the invention is obtainedwhich contains one or more protecting groups. Alternatively, aderivative according to the invention which contains one or moreprotecting groups can also be obtained by providing one or more of thefunctional groups in a derivative according to the invention whichcontains at least one further functional group, preferably selected fromhydroxyl groups, acid functions which are capable of salt formation andacid functions in the form of a salt, with a protecting group.Derivatives according to the invention as described above which containat least one protecting group or a functional group which is providedwith a protecting group are referred to below as protected derivatives.

For the purposes of this invention, protected derivatives are thereforetaken to mean, in particular, derivatives according to the invention inwhich the covalently bonded acid contains one or more further functionalgroups, in particular hydroxyl and/or acid groups, in which one or moreof the further functional groups are protected as described above, i.e.is provided with a protecting group. Further functional groups for thepurposes of this invention are the functional groups and in particularthe hydroxyl and/or acid groups of the acids covalently bonded inaccordance with the invention which do not effect the covalent bond totheN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideradical.

Examples of preferred protected derivatives are derivatives according tothe invention in which the further functional groups are in the form ofone or more hydroxyl and/or one or more acid groups, where all or someof the hydroxyl groups are in acetalated form and/or all or some of theacid groups are in the form of the alkyl esters and in particular themethyl esters.

Preferred protected derivatives, i.e. derivatives provided with one ormore protecting groups, are compounds of the formula Iaa

-   -   and compounds of the formula Ibb

-   -   in which all radicals R* are selected, independently of one        another, from H and R′CO, and the radicals R′ and R″ are as        defined above, with the proviso that at least one of the        radicals R*, R′ and R″ in each of the compound of the formula        Iaa and the compound of the formula Ibb is not H,    -   and the salts and solvates thereof.

Very particularly preferred protected derivatives are the compounds ofthe formula Iaa and the salts and solvates thereof.

For the purposes of this invention, protected derivatives are preferablythose in which all radicals R*, R′ and R″ are not H or, if two or moreradicals selected from R*, R′ and R″ are present, those in which onlyone or two of the radicals R*, R′ and R″ are H and preferably those inwhich only one of the radicals R*, R′ and R″ is H.

The derivatives according to the invention interact, as described above,intensively with the organism, in particular the enterohepaticcirculation. Experiments have shown that protected derivatives asdescribed above can also be modified in full or part into derivativesaccording to the invention or converted into the latter underphysiological conditions, for example by interactions as describedabove. Thus, protected derivatives can be regarded as having anequivalent action to the derivatives according to the invention and thusas prodrugs in the sense of this invention. The present invention thusalso relates to the protected derivatives which can be employed, asdescribed below, as active ingredient for the treatment of diseases andin particular for the preparation of medicaments and/or pharmaceuticalpreparations.

Preferred prodrugs are protected derivatives in which the covalentlybonded acid is selected from dibasic carboxylic acids and monobasichydroxycarboxylic acids. Preferred monobasic hydroxycarboxylic acids inthis sense are sugar acids.

Particularly preferred prodrugs are derivatives according to theinvention in which the covalently bonded acid is selected from sugaracids and in which one or more of the further functional groups asdescribed above contain a protecting group as described above.Particularly preferred prodrugs are derivatives according to theinvention in which all or some of the hydroxyl groups are in acetalatedform and/or in which all or some of the acid groups are in the form ofthe alkyl esters and in particular the methyl esters.

The compounds of the general formula I and physiologically acceptablesalts thereof can therefore be used for the preparation ofpharmaceutical preparations by converting them into a suitable dosageform together with at least one excipient or adjuvant and, if desired,with one or more further active ingredients.

The present invention therefore relates to a process for the preparationof pharmaceutical compositions as described above and in particular to aprocess for the preparation of pharmaceutical preparations in which atleast one derivative according to the invention and at least one furthercompound selected from excipients, adjuvants and pharmaceutical activeingredients which are different from derivatives according to theinvention are converted, using one or more mechanical process steps,into a pharmaceutical composition which is suitable as dosage form foradministration to patients. Suitable mechanical process steps are knownto the person skilled in the art and include, inter alia, mixingprocesses, grinding processes, dissolution processes, sieving processes,homogenisation, drying, pressing, tabletting, coating and/orsugar-coating.

The present invention therefore also relates to the pharmaceuticalcompositions obtainable by this process.

For the purposes of the invention, suitable dosage forms are preferablytablets, coated tablets, capsules, syrups, juices, drops, suppositories,plasters, solutions, in particular parenteral solutions, suspensions,creams, ointments, emulsions and implants which comprise at least onederivative according to the invention and/or a salt or solvate thereof.

The invention therefore also relates to a pharmaceutical preparationcharacterised by a content of at least one derivative according to theinvention and/or one of its salts, in particular physiologicallyacceptable salts, as described above, and in particular pharmaceuticalpreparations as described above for the treatment and/or prophylaxis ofone or more of the diseases described above.

The present invention also relates to a pharmaceutical preparationcomprising at least one derivative according to the invention and/or asalt or solvate thereof and at least one further active ingredient whichis different from the derivatives according to the invention and ispreferably also different fromN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide.

The present invention also relates to a pharmaceutical preparationcomprising at least one derivative according to the invention and/or asalt or solvate thereof and at least one further active ingredient,preferably an active ingredient which acts as appetite suppressant.

The preparations obtained in this way can be employed as medicaments inhuman or veterinary medicine. Suitable carrier substances are organic orinorganic substances which are suitable for enteral (for example oral orrectal) or parenteral administration and do not react with the novelcompounds, for example water, vegetable oils, benzyl alcohols,polyethylene glycols, glycerol triacetate and other fatty acidglycerides, gelatine, soya lecithin, carbohydrates, such as lactose orstarch, magnesium stearate, talc or cellulose.

Suitable for oral administration are, in particular, tablets, coatedtablets, capsules, syrups, juices or drops. Of particular interest arefilm-coated tablets and capsules having gastric juice-resistant coatingsor capsule shells. Suitable for rectal administration are suppositories,and suitable for parenteral administration are solutions, preferablyoil-based or aqueous solutions, furthermore suspensions, emulsions orimplants.

The active ingredients claimed in accordance with the invention may alsobe lyophilised and the resultant lyophilisates used, for example, forthe preparation of injection preparations.

The preparations mentioned may be sterilised and/or comprise adjuvants,such as preservatives, stabilisers and/or wetting agents, emulsifiers,salts for modifying the osmotic pressure, buffer substances, colorantsand/or aroma substances. They may, if desired, also comprise one or morefurther active ingredients, for example one or more vitamins, diureticsor antiphlogistics.

The derivatives according to the invention are generally administeredanalogously to other known preparations which are commercially availablefor the claimed indications, preferably in doses of between about 1 mgand 70 mg, in particular between 5 and 50 mg per dosage unit. The dailydose is preferably between about 0.02 and 30 mg/kg, in particularbetween 0.2 and 0.6 mg/kg of body weight.

However, the specific dose for each individual patient depends on a verywide variety of factors, for example on the efficacy of the specificcompound employed, on the age, body weight, general state of health,sex, on the diet, on the time and method of administration, on theexcretion rate, medicament combination and severity of the particulardisease to which the therapy applies. Oral administration is preferred.

EXAMPLES Preparation of6-(1-{[(2,2-diphenylethanoyl)methylamino]phenylethyl}pyrrolidin-3-yloxy)-3,4,5-trihydroxytetrahydropyran-2-carboxylicacid (Compound Ia)

-   a) A mixture of 2.0 g (4.434 mmol) of    N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide    and 1.76 g (4.430 mmol) of glycosyl halide A is initially introduced    in 50 ml of acetonitrile, an excess of a silver salt, for example    silver perchlorate or silver carbonate, is added, and the reaction    mixture is stirred overnight at room temperature. After filtration    through kieselguhr, the solvent is removed under reduced pressure,    and the residue is purified by chromatography (flash chromatography    on SI-60 with toluene/methanol=9:1→4:1 as eluent; R_(f)=0.54,    toluene/MeOH 4:1), giving 190 mg of compound B.-   b) 110 mg (0.151 mmol) of compound B are dissolved in 4 ml of    1,4-dioxane, 0.755 ml of 1N sodium hydroxide solution is added, and    the mixture is stirred at room temperature. Monitoring of the    reaction by HPLC shows that the reaction is complete after stirring    for about three hours. The reaction mixture is subsequently    neutralised using 1N hydrochloric acid and evaporated to dryness.    The resultant residue can be purified by preparative HPLC on RP-18,    giving 65 mg of compound (Ia) (R_(t)=31.65 min (Lichrospher 1000,    RP-18, 5 μm, gradient elution (A:B from 99:1 to 1:99 in 1 hour; A:    H₂O+0.3% TFA (=trifluoroacetic acid); B: CH₃CN/H₂O (80:20)+0.3%    TFA).

Alternatively, the synthesis can be carried out as a one-pot reaction inwhich chromatographic purification of the reaction product from step a)is omitted. In this case, the reaction mixture is filtered when thereaction is complete, and the solvent is removed under reduced pressure.If desired after the resultant residue has been taken up in water andextracted with dichloromethane or methyl acetate, sodium hydroxidesolution can be added, as described in step b), and the mixture isstirred at room temperature. The resultant crude product of6-(1-{[(2,2-diphenylethanoyl)methylamino]phenylethyl}pyrrolidin-3-yloxy)-3,4,5-trihydroxytetrahydropyran-2-carboxylicacid can be worked up as described under step b).

Preparation ofmono-{1-[2-(diphenylacetylmethylamino)-2-phenylethyl]pyrrolidin-3-yl}sulfate(Ib)

0.9 gram (2.0 mmol) ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamideis initially introduced in 10 ml of dichloromethane, and 150 μl (2.0mmol) of chlorosulfonic acid are added. After a reaction time of twodays, the solvent is distilled off, the resultant residue is triturateda number of times with acetone and the supernatant acetone decanted off,and the resultant crystals are filtered off under reduced pressure anddried in air. Drying in air gives 740 mg (74.3% of theory) ofcrystalline solid of compound (Ib) having a melting point of 268° C.

Preparation ofN-{2-[(3S)-3-acetoxy-1-pyrrolidinyl]-(1S)-1-phenylethyl}-2,2-diphenyl-N-methylacetamide(Compound Ic)

30 ml of acetic anhydride and 15 ml of triethylamine are added to 5.0grams (11.0 mmol) ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide,hydrochloride, and the mixture is heated for two hours on a steam bath.The reaction mixture is subsequently evaporated to dryness, and theresidue is taken up in ether and washed with bicarbonate solution. Theorganic phase is subsequently dried, and the solvent is distilled off.The resultant residue is purified by column chromatography on silica gelwith diethyl ether/methanol (99:1) as eluent. The resultant crudeproduct ofN-{2-[(3S)-3-acetoxy-1-pyrrolidinyl]-(1S)-1-phenylethyl}-2,2-diphenyl-N-methylacetamidecan be purified further by taking up in diethyl ether, precipitation byaddition of ethereal HCl, filtering-off of the resultant crystals underreduced pressure, washing of the crystals with ether and drying in air(R_(f)=0.6 (TLC on silica gel 6 F₂₅₄ with dichloromethane/methanol (8:2)as eluent)).

1. A method of treating a subject having irritable bowel syndrome,comprising administering an effective dose ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxy-pyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidecovalently bonded to at least one acid, and/or a salt ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxy-pyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidecovalently bonded to at least one acid, to a subject having irritablebowel syndrome, thereby treating irritable bowel syndrome.
 2. A methodof treating a subject having functional diarrhea, comprisingadministering an effective dose ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxy-pyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidecovalently bonded to at least one acid, and/or a salt ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxy-pyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidecovalently bonded to at least one acid, to a subject having functionaldiarrhea, thereby treating functional diarrhea.
 3. A method of treatinga subject having post-operative ileus, comprising administering aneffective dose ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxy-pyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidecovalently bonded to at least one acid, and/or a salt ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxy-pyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidecovalently bonded to at least one acid, to a subject havingpost-operative ileus, thereby treating post-operative ileus.
 4. Themethod of claim 1, wherein the acid is covalently bonded via the3-hydroxypyrrolidine group of N-methyl-N-[(1S)-1phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide.5. The method of claim 1, wherein the acid is a carboxylic acid,hydroxycarboxylic acid or inorganic oxygen acid.
 6. The method of claim1, wherein the acid is a dibasic carboxylic acid, monobasichydroxycarboxylic acid, or dibasic inorganic oxygen acid.
 7. The methodof claim 6, wherein the monobasic hydroxycarboxylic acid is a sugaracid.
 8. The method of claim 7, wherein the sugar acid is glucuronicacid.
 9. The method of claim 6, wherein the dibasic inorganic oxygenacid is sulfuric acid.
 10. The method of claim 1, wherein6-(1-{[(2,2diphenylethanoyl)methylamino]phenylethyl}pyrrolidin-3-yloxy}-3,4,5-tri-hydroxytetrahydropyrarr-2-carboxylic acid,mono-{1[2-(diphenylacetyl-methylamino)-2phenylethyl]pyrrolidin-3-yl}sulfate,N-{2-[(3S)-3-acetoxy-1-pyrrolidinyl]-(1S)-1-phenylethyl}-2,2-diphenyl-N-methylacetamide,or a salt thereof is administered.
 11. A method of treating irritablebladder syndrome, comprising administering an effective dose ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxy-pyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidecovalently bonded to at least one acid, and/or a salt ofN-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxy-pyrrolidin-1-yl)ethyl]-2,2-diphenylacetamidecovalently bonded to at least one acid to a subject having irritablebladder syndrome, thereby treating irritable bladder syndrome.
 12. Themethod of claim 11, wherein the acid is covalently bonded via the3-hydroxypyrrolidine group of N-methyl-N-[(1S)-1phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide.13. The method of claim 11, wherein the acid is a carboxylic acid,hydroxycarboxylic acid or inorganic oxygen acid.
 14. The method of claim11, wherein the acid is a dibasic carboxylic acid, monobasichydroxycarboxylic acid, or dibasic inorganic oxygen acid.
 15. The methodof claim 14, wherein the monobasic hydroxycarboxylic acid is a sugaracid.
 16. The method of claim 15, wherein the sugar acid is glucuronicacid.
 17. The method of claim 14, wherein the dibasic inorganic oxygenacid is sulfuric acid.
 18. The method of claim 11, wherein6-(1-{[(2,2diphenylethanoyl)methylamino]phenylethyl}pyrrolidin-3-yloxy}-3,4,5-tri-hydroxytetrahydropyrarr-2-carboxylic acid,mono-{1[2-(diphenylacetyl-methylamino)-2phenylethyl]pyrrolidin-3-yl}sulfate,N-{2-[(3S)-3-acetoxy-1-pyrrolidinyl]-(1S)-1-phenylethyl}-2,2-diphenyl-N-methylacetamide,or a salt thereof is administered.
 19. The method of claim 2, whereinthe acid is covalently bonded via the 3-hydroxypyrrolidine group ofN-methyl-N-[(1S)-1phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide.20. The method of claim 2, wherein6-(1-{[(2,2diphenylethanoyl)methylamino]phenylethyl}pyrrolidin-3-yloxy}-3,4,5-tri-hydroxytetrahydropyrarr-2-carboxylic acid,mono-{1[2-(diphenylacetyl-methylamino)-2phenylethyl]pyrrolidin-3-yl}sulfate,N-{2-[(3S)-3-acetoxy-1-pyrrolidinyl]-(1S)-1-phenylethyl}-2,2-diphenyl-N-methylacetamide,or a salt thereof is administered.
 21. The method of claim 3, whereinthe acid is covalently bonded via the 3-hydroxypyrrolidine group ofN-methyl-N-[(1S)-1phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide.22. The method of claim 3, wherein the acid is a carboxylic acid,hydroxycarboxylic acid or inorganic oxygen acid.
 23. The method of claim3, wherein 6-(1-{[(2,2diphenylethanoyl)methylamino]phenylethyl}pyrrolidin-3-yloxy}-3,4,5-tri-hydroxytetrahydropyrarr-2-carboxylic acid,mono-{1[2-(diphenylacetyl-methylamino)-2phenylethyl]pyrrolidin-3-yl}sulfate,N-{2-[(3S)-3-acetoxy-1-pyrrolidinyl]-(1S)-1-phenylethyl}-2,2-diphenyl-N-methylacetamide,or a salt thereof is administered.